Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 2019 Mar;567(7748):341-346
Date
03/08/2019Pubmed ID
30842654Pubmed Central ID
PMC6655586DOI
10.1038/s41586-019-0993-xScopus ID
2-s2.0-85063281637 (requires institutional sign-in at Scopus site) 193 CitationsAbstract
Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F0F1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents.
Author List
Shi Y, Lim SK, Liang Q, Iyer SV, Wang HY, Wang Z, Xie X, Sun D, Chen YJ, Tabar V, Gutin P, Williams N, De Brabander JK, Parada LFAuthor
Daochun Sun PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllograftsAnimals
Astrocytes
Cell Line, Tumor
Fibroblasts
Glioblastoma
Humans
Hydrogen-Ion Concentration
Mice
Mitochondrial Membrane Transport Proteins
Mitochondrial Membranes
Neoplasm Transplantation
Organ Specificity
Oxidative Phosphorylation
Proton-Motive Force
Proton-Translocating ATPases
Xenograft Model Antitumor Assays
